Operative treatment of nonunions in the elderly: Clinical and radiographic outcomes in patients at minimum 75 years of age

Background
 Limited information exists on nonunion treatment in the elderly. This retrospective study evaluates whether results of operative treatment of nonunion of the humerus or femur in patients aged ≥ 75 years are comparable to those in younger patients. Methods We identified patients age ≥ 75 years with a nonunion of humerus or femur treated with open reduction and internal fixation. The Non-Union Scoring System was calculated. Complications, clinical outcome, and radiographic findings were assessed. Primary endpoint was nonunion healing. A literature review compared time to healing of humeral and femoral nonunion in younger populations. Results We identified 45 patients treated for a nonunion of humerus or femur with > 12 months follow-up. Median age was 79 years (range 75–96). Median time to presentation was 12 months (range 4–127) after injury, median number of prior surgeries was 1 (range 0–4). Union rate was 100%, with median time to union 6 months (range 2–42). Six patients underwent revision for persistent nonunion and healed without further complications. Conclusions Using a protocol of debridement, alignment, compression, stable fixation, bone grafting and early motion, patients aged 75 years or older can reliably achieve healing when faced with a nonunion of the humerus or femur. Level of Evidence: IV.


Background
Musculoskeletal problems in the elderly are seldom fatal, but quality of life and function is often severely affected after impaired fracture healing. Fortunately, bone has intrinsic capacity to heal after a fracture [1]. This reparative (almost regenerative) potential is surprisingly well maintained throughout life [2]. The complex but wellorchestrated events seen after a fracture closely resemble bone development during embryogenesis and, in the majority of cases, leads to complete healing and restoration of pre-fracture mobility and function [3]. A small subset of patients will develop a nonunion [4]. To complicate matters, there is no consensus as to what defines van Trikt et al. BMC Geriatrics (2022) 22:985 a nonunion. One pragmatic definition is "a fracture that will not heal without surgical intervention" [5].
Risk factors for development of a nonunion are numerous. There are fracture-related factors (e.g., open injuries, and devitalized segments), patient-related factors (ex. nutrition, comorbidities, and smoking), and medication factors. Additionally, there are surgeon-related factors such as surgical technique (ex. biologically friendly versus extensile dissections), mechanical stability provided, and quality of reduction [6]. Finally, infection can play a significant role, especially if the nonunion presents after attempted surgical intervention.
Whether age is an independent risk factor for nonunion remains unclear. There is evidence that bone repair is delayed in the elderly compared to younger patients [7][8][9]. Recent studies (animal and human) elucidated small but potentially important differences between fracture healing in these two age groups [9][10][11]. With increased aging, there are less mesenchymal stem cells (MSC) or osteoprogenitor cells [7,8,[11][12][13]. Stem cells from elderly patients produce less bone than those from younger individuals [14]. MSCs in the elderly differentiate more into adipocytes rather than osteoblasts [15]. Additionally, recent studies suggest an increased inflammatory state in the elderly, known as inflammaging, triggers skeletal stem/progenitor cell dysfunction and cell senescence [12,13]. Despite progress made during recent decades in fracture treatment, the overall incidence of non-unions remains 2-5% for all fracture types [16,17]. Higher incidence of failure in nonunion surgery is expected in elderly given their delayed bone repair. Furthermore, the number of elderly patients requiring nonunion treatment will grow due to rising life expectancy [18,19].
In most patients, a nonunion is a disabling condition resulting in pain, reduced activity levels, and inability to return to the pre-injury functional status [20]. A nonunion may even have a higher impact upon the elderly population, who often have compromised self-reliance and mobility, and lead to increased need for long-term nursing homecare, decreased quality of life, social isolation, depression, and decreased self-confidence [21].
The goal of nonunion surgery in the elderly is achieving the highest functional recovery. This can be accomplished with prosthetic replacement in some cases. Prosthetic replacement has a role in nonunion of the femoral neck, distal femur, as well as in the proximal humerus and distal humerus. However, most nonunions will require formal open reduction and internal fixation (ORIF) and potentially bone grafting [22,23]. There are many challenging issues for any type of ORIF in the elderly, which often include a combination of decreased soft tissue quality, prior scar tissue, poor bone stock, and joint stiffness of the affected limb. The same age-related comorbidities that compromise fracture healing (e.g., diabetes, malnutrition, osteoporosis, osteopenia, and polypharmacy including chronic opioid use) increase the complexity level of operative fracture treatment and after-care in the elderly [7,9,18,24].
Although many studies have reported on patient outcomes following nonunion treatment, to date no studies have reported outcomes of nonunion treatment in patients aged 75 years or older [25,26]. Specifically, we were interested in whether treatment of nonunions of the humerus and femur resulted in similar osseus union rates and time to union in the elderly as compared to younger cohorts reported in the literature. Thus, the first purpose of this study was to assess outcomes of operative nonunion treatment in patients aged 75 years or older. We assessed the rate of radiographic and clinical time to osseous union, subsequent surgeries, and complications. We then compared our results with findings from the literature.

Methods
Institutional Review Board approval was obtained for this retrospective research study. All patients aged 75 years or older with an operatively treated nonunion of the humerus or femur between 1996-2019 were identified in two tertiary referral centers (Hospital for Special Surgery and Amsterdam Medical Center). Other nonunion locations were excluded (n = 15). All patients were treated by three fellowship-trained orthopedic trauma surgeons on this study (DLH, PK, and DSW). Exclusion criteria consisted of pathologic fractures and follow-up less than 12 months (n = 30). All data were prospectively recorded in orthopedic trauma databases. The fracture leading to the nonunion was classified according to the AO/OTA classification (including the periprosthetic classification) [27]. Nonunion type was classified according to Weber and Çech and the Non-Union Scoring System (NUSS) according to Calori et al. which combines nonunion type and previous treatment with patient characteristics (e.g., ASA-score, comorbidity, medication, blood tests) [28,29]. The NUSS ranges from 0-100 points, with 0-25 points representing a straightforward nonunion. A score of 75-100 indicates the need for amputation, arthrodesis or prosthetic replacement [30,31]. Radiographic assessment included presence or absence of bone healing (cortical bridging of at least 3 cortices) using standard radiographs and/ or CT-scan [32]. Subsequent revision surgery to achieve bony union and post-operative complications were also documented. Patients were seen at regular intervals (6 weeks, 3, 6, 12 months). Clinical outcome was based on pain and ability to weight-bear (for femur nonunion). Patient demographics are listed in Table 1.

Surgical technique
The type of surgery was at the discretion of the treating surgeon involved in their care. Two of the three treating surgeons in this study were fellowship trained by the third. Given this training background, there were only minor differences in surgical tactics and choice of fixation. All surgeries included infection screening using tissue sampling before administration of intravenous antibiotics (2gm cephalosporin). For distal and shaft nonunion, a tourniquet was used at 250 mm Hg up to a maximum of 2 h. Whenever possible, the previous scar tissue was utilized for the surgical approach. After exposure, all failed or loose hardware was removed. For oligotrophic and atrophic nonunions, intervening soft tissues were removed with a combination of scalpel, curette or ronguer. The medullary canal was drilled open, or the sclerotic end cap was removed with an oscillating saw. Debridement progressed until healthy bleeding bone was visible at both nonunion ends. For well-aligned hypertrophic nonunion, the intervening tissue of the nonunion was left intact. For distal femur and distal humerus nonunion with limited motion due to contracture and/or adhesions, a formal soft tissue release was performed [23,33]. Reduction and temporary fixation was provided by K-wires, reduction clamps, and/or small plates. Depending on nonunion type and location and prior fixation, definitive fixation consisted of compression plating or nailing. When plating was selected, the surgical strategy consisted of, whenever possible, relatively long plates with hybrid fixation and compression across the nonunion site with rigid fixation [34]. Plating was performed in all humeral nonunions. We strongly prefer plating, as results of intramedullary nails for upper extremity long bone nonunions are potentially inferior [35,36] For midshaft femur nonunion, either plates or nails were selected depending on nonunion type and surgeon preference. For nonunion in the meta-diaphyseal area of the femur, plating was performed.
Bone graft utilization was dependent on nonunion type. In most oligotrophic nonunions, and in all atrophic nonunions, bone graft was utilized. Iliac crest bone graft (ICBG) was used throughout the study period, as was demineralized bone matrix (DBM, Johnson&Johnson/DePuy/Synthes, Paoli, PA, and Osteotech, Eatontown, NJ). Bone morphogenetic proteins (BMP-2; Infuse, Medtronic Minneapolis, MN) was used in isolated cases. For large defects, fibula allograft or tricortical ICBG were used for structural support.

Literature search
A literature search was completed (PubMed/Google Scholar) using search terms "nonunion", "non-union", "delayed union", "femur", "humerus". Selection criteria were: i) time to union being measured, ii) a minimum of 6 patients, iii) age provided, and iv) English language. We compared our results with published findings in younger patients. A multi-variate regression analysis (corrected for sample size) was run to predict time to union based on age and location (Fig. 1).

Outcomes
After the index surgery, 39 patients (86.7%) achieved osseous union at median time of 6 months (range 2-37); (Tables 2 and 3). Median time to union was longer in the humerus (6 months) than the femur (5 months). This may be explained by the characteristics of the humerus nonunion cohort, classified as either atrophic (56%) or oligotrophic (44%), as compared to the femoral nonunion group where 28% represented a hypertrophic nonunion.

Complications and additional surgery
Six patients (13.3%) required revision surgery for persistent nonunion (Tables 2 and 3). In five (all femoral), a single revision was performed; in one (humerus shaft) a planned two-stage revision was completed. Revision surgeries took place at a median of 6 months (range 2-13) after the index surgery. The nonunion in these 6 patients ultimately healed at a median of 10.5 months (range 4-42) after the index nonunion surgery. Median follow-up after the index and revision surgery was 41 months (range 12-137) and 38 months (range 13-143), respectively. One patient developed a post-operative radial nerve palsy, which fully recovered. One patient (95-year-old female) sustained an intra-operative distal humerus fracture below the plates used for fixation of the diaphyseal humerus nonunion. The fixation was modified to include a second plate. She healed uneventfully (Fig. 2). Three patients (6.7%) requested hardware removal. One patient (2.2%) required a total hip arthroplasty for a femoral neck fracture after the distal femoral periprosthetic nonunion healed. There was one infection (2.2%) after the index procedure, which was treated with debridement, antibiotics, and placement of calcium-sulfate pellets (OSTEOSET, Wright Medical Technology Inc. Arlington, TN, USA). The infection cleared and the nonunion healed after the second stage of the revision. Four patients (8.9%) had "surprise positive cultures". The isolated bacteria (Cutibacterium acnes and Coagulase-negative staphylococci) were treated with culture-specific antibiotics. Three of these healed without additional surgery. One patient with a proximal femoral nonunion (Coagulase-negative staphylococci detected at index procedure), required revision ORIF. She healed 5 months later.

Literature comparison with our results
We compared our current results with literature on younger femur and humerus nonunion groups (Table 4) [20,23,. This table provides a comparative framework (Fig. 1). We ran a multi-variate regression analysis of

Discussion
In most patients, a nonunion is a disabling condition resulting in pain, reduced activity, and inability to return to pre-injury functional status [6]. The goal of nonunion surgery is to achieve a pain-free healed bone with the highest functional recovery. Many studies have reported on techniques and complications following nonunion treatment [20,23,.
To date, few have reported on nonunion treatment specifically in older patients [26,64,65]. To the best of our knowledge, no studies have restricted their findings to nonunion patients aged over 74 years.
In general, the spatiotemporal sequence of fracture healing is similar in elderly and younger populations, but the progression is protracted [66]. The cause of this is multifactorial. The expression of bone producing cells and regulation of the surrounding environment change with aging. Osteo-anabolic effects of the Wnt/ BMP pathway are decreased, lowering differentiation       [67,68]. Further, the functional abilities of not only MSC but also those of macrophages (important for bone healing) are impaired [5,12]. Conversely, the proinflammatory cytokines such as TNF-a and Il-6 lead to increased osteoclastogenesis and increased bone resorption [67,68].
The surrounding supportive tissue is affected by aging as well. Fracture healing requires vascularity; expression of angiogenic factors HIF-1A and VEGF has been shown to differ between young versus old animals [69]. Further, the endothelial precursor cells (EPC) required for new blood vessel formation are compromised [68]. Additionally in females specifically, the postmenopausal estrogen deficiency negatively affects bone healing response [70]. It is well accepted that density of bone decreases with age, but recent studies showed osteoporosis and decreased bone density are not risk factors for nonunion when matched for age and sex [71,72]. These findings are confirmed in a large retrospective nonunion study [7]. The cause of nonunion in patients with osteoporosis is likely multifactorial and includes age-related changes in bones as well as challenges in achieving stable internal fixation [73].
The exact incidence of nonunion in older patients is disputed, but given the macro trend of increased aging, they will continue to occur. An examination of > 47,000 Medicare patients aged > 75 years showed a lower rate of nonunion compared to those < 70 [19]. Another study by Mills et al. showed not only that the total number of nonunion in this age category of patients is lower than previously thought, but also that the in the 75-85 year age bracket was 1.2% versus 3% in the younger group (25-44 years) [74].
Concerns in the very elderly include poor bone stock and co-morbidities jeopardizing surgical outcomes. Fortunately, our results and those of others demonstrate good and reproducible outcomes of operative treatment for elderly nonunion patients [25]. Similar to our younger nonunion patients, we utilized a protocol of debridement, reduction, stable fixation, bone grafting, and early motion [23,38,43,44,51,53,54,56].
Few clinical reports focus on nonunion in seniors. Zura et al. performed a prospective cohort study of 2.5 million United States Medicare patients. Of these, 47,437 had a fracture or nonunion. Patients with a fracture but without a nonunion were older (75 years) versus those with a nonunion (69.2 years) [19]. Taormina et al. also published a nonunion study, but reported on a younger nonunion population than ours (64 years or older) [64]. In their work, which focused on nonunions of forearm, femur, humerus, clavicle, tibia, foot and ankle, they found patients age was not associated with achieving union and, importantly, that advanced age was not associated with worse outcomes.
Finally, Tanner et al. reported a matched pair analysis on outcome of lower limb nonunion treatment in patients younger or older than 60 years [26,65]. Treatment was according to the diamond concept. Advanced age did not negatively influence outcome of nonunion surgery [65].
This study has limitations. Although these patients are a prospectively documented cohort in our orthopedic trauma database, pre-operative or post-operative patient-based scores were unavailable. Therefore, clinical improvement after operative treatment could not be assessed. However, osseous union is a logical endpoint after nonunion treatment and it is well Last procedure = index procedure or revision procedure; * = follow-up time was calculated from index procedure onwards or revision procedure onwards; ** = time to union was calculated from index procedure onwards or revision procedure onwards Median time to union in months** (range) 6 (2 -42) 6 (2 -37) 6 (2 -42) known that clinical and radiological outcome correlate regardless of patient age [65]. Additionally, since all three orthopedic surgeons are experienced nonunion surgeons, the results may not be easily reproducible in a general orthopedic setting. Also, a large group of 30 patients (14 humeral nonunions and 16 femoral nonunions) were excluded because they had shorter than 12 months follow-up due to large traveling distance, concomitant disease, or death. This may have led to selection bias. We included the Weber and Çech classification in this series as it is a part of the NUSS scoring system and many surgeons still refer to it in practice. In reality, we feel the Weber and Çech system likely has little applicability to modern nonunion series as most patients (80% in this series) have already undergone ORIF and are highly unlikely to show the classic historical patterns of atrophic and hypertrophic nonunions seen when many long bone fractures were treated nonoperatively. We have done our best to classify all of the patients into one of the 3 groups, however, nonunions after ORIF usually display some level of callus formation on plain film and CT-scans, and the difference amongst hyper, oligo, and atrophic is quite subjective. Table 4 Literature search showing union time (average, months) and age (average, years) based on nonunion location Fe = femur; Fe* = femur periprosthetic; Hu = humerus; * = average age was used for the statistical analysis and was calculated from index procedure onwards or revision procedure onwards; * = average time to union was used for the statistical analysis and was calculated from index procedure onwards or revision procedure onwards Peng et al. [52] Fe Furthermore, use of bone grafting was not standardized and amount of graft in relation to defect size was unknown. Comparing contributions of BMP versus DBM versus allograft and/or autologous bone graft was not part of the study. Autologous bone graft continues to be the gold standard for bone grafting [75]. Lastly, the reviewed literature did not have a clear-cut definition for nonunion so comparing our results with existing studies was difficult.
The series has several notable strengths. All patients were treated using a standardized surgical protocol consisting of debridement, reduction, and stable fixation., inclusion of the NUSS, radiographic evaluation by a musculoskeletal radiologist, and > 12 months follow-up. Another benefit of the study is inclusion of the NUSS.
Rather than reporting a mixed cohort of nonunion locations, we limited our study to the two most frequent occurring nonunion (humerus and femur) in the elderly. While others reported on nonunion in the elderly, their minimum inclusion age was much lower than ours [26,64,65]. We believe our group represents a different age bracket. Lastly, it represents two geographically diverse groups with very different health care systems (European and American respectively) showing equal outcomes. This suggests that these results are reproducible in different health care systems.
As we look to the future, potential treatment opportunities to accelerate fracture and nonunion healing may be different for the elderly as the native MSC and endothelial precursor cells needed for new blood vessel formation are compromised in number and/or function. Further options may involve bone anabolic pharmaceuticals (parathormone, growth factors such as BMP), reduction of senescent progenitor cells, or decreasing the inflammaging state in the elderly with a low-grade, non-steroidal anti-inflammatory drugs (NSAID). [13,68] Despite enormous progress and promising results of using these adjuncts in animal studies, clinical success has been lacking. This should be kept in mind when using these adjuncts, as this is a vulnerable group of patients that attracts a highly competitive bone regeneration industry that is often based on unsupported claims of success [24].

Conclusions
Following a standardized protocol of aggressive debridement, anatomic alignment, stable fixation with compression, liberal use of bone grafting, and early motion was found to reliably achieve bony union in the elderly nonunion patient.
Given these results, we recommend nonunion surgery in the geriatric patient population after thorough risk assessment and preoperative medical and surgical optimization is achieved. Advanced patient age should not be a contra-indication for nonunion surgery.